According to the World Health Organization, 15 million people worldwide suffer a stroke every year. Of these, 5 million die and another 5 million are left permanently disabled, placing a heavy burden on families, communities, and governments. While patients with symptoms and signs of acute ischemic stroke represent the easily recognized "tip of the iceberg", it is well accepted that the deleterious effects of ischemic brain vascular disease begin well before clinical symptoms become apparent. Indeed, ischemic brain vascular abnormalities detectable by magnetic resonance imaging (MRI), including white matter hyperintensities (WMH) and silent brain infarcts (SBI), are common in asymptomatic populations beginning in middle age. Both are strongly and independently associated with increased risk of subsequent ischemic stroke, and there is evidence that they may share common pathogenic mechanisms. The molecular basis of these relationships is, however, unknown. Advances in the genome sciences afford new opportunities to identify genes for ischemic brain vascular injury through genome-wide linkage disequilibrium mapping. The proposed research represents a collaborative effort to use existing specimens, previously-collected genotype data on a genome-wide collection of single nucleotide polymorphisms (SNPs), high-quality phenotypic data, and state-of-the-art analytical methods to identify and replicate genetic effects influencing ischemic brain vascular injury in the clinical and subclinical stages. The primary setting is that of the Atherosclerosis Risk In Communities (ARIC) study, a prospective study of 15,792 African-Americans and European-Americans 45-64 years of age at baseline to investigate the etiology and natural history of cardiovascular disease and its risk factors. Genotype data on a collection of 906,600 SNPs is available on the whole cohort and will be used to conduct whole genome association analyses of incident clinical ischemic stroke and subclinical ischemic brain vascular injury defined by presence on MRI of WMHs or SBIs. Replication of results will be facilitated through meta-analyses of genome-wide association data on the same phenotypes collected in the Framingham Heart Study and the Cardiovascular Health Study (CHS), as well as follow-up genotyping and association analyses in additional cohorts, including the Genes Associated with Stroke Risk and Outcomes Study (GASROS) and the Genetic Network Of Arteriosclerosis (GENOA). The proposed research provides a unique opportunity to identify novel genes influencing ischemic brain vascular injury in the clinical and subclinical stages, and to begin to unravel the molecular basis of the relationship between overt and covert brain vascular disease. PUBLIC HEALTH RELEVANCE: Advances in the genome sciences afford new opportunities to identify genes for ischemic brain vascular injury through genome-wide linkage disequilibrium mapping. The proposed research represents a collaborative effort to use existing specimens, previously-collected genotype data on a genome-wide collection of single nucleotide polymorphisms (SNPs), high-quality phenotypic data, and state-of-the-art analytical methods to identify and replicate genetic effects influencing ischemic brain vascular injury in the clinical and subclinical stages.